The field of invention is Vibrio cholerae vaccines.
After more than 100 years of research on cholerae, there remains a need for an effective cholerae vaccine. There have been six pandemics of this disease caused by strains of V. cholerae belonging to the "Classical" biotype. The etiological agents of the current (seventh) pandemic belong to the "El Tor" biotype. Recently the seventh pandemic has extended to a new locale, that of South America. Beginning in January of 1991, an epidemic of cholerae resulted in greater than 250,000 cases and over 2,000 deaths in Peru, Ecuador, Columbia, and Chile. In November of 1992, an antigenically distinct, non-01 form of V. cholerae emerged in India and Bangladesh and within eight months caused an estimated 500,000 cases and 6,000 deaths. The pandemic potential of this new strain, designated serogroup 0139 synonym "Bengal", seems assured and is a new cause of concern throughout the developing world. These recent experiences underline the need for effective cholera vaccines against disease due to 01 serogroup El Tor biotype of V. cholerae and Bengal 0139 serogroup of V. cholerae.
The major issues which must be overcome to produce effective cholerae vaccines are safety, stability and a high degree of antigenicity. Because natural infection by and recovery from cholerae induces immunity lasting at least 3 years, much effort has been made to produce live, attenuated cholerae vaccines that, when administered orally, would mimic the disease in its immunization properties, but would not cause adverse symptoms or reactions in the immunized individual (i.e., vaccines which display low reactogenicity). Vaccines of this type involve deletion mutations that inactivate the gene encoding the A subunit of cholerae toxin, a protein which is responsible for most of the diarrhea seen in this disease. See, for example, Mekalanos, U.S. Pat. Nos. 5,098,998 and 4,882,278, and Kaper et al., U.S. Pat. No. 4,935,364, hereby incorporated by reference. While both oral, killed whole cell vaccines and several live, attenuated cholerae vaccines have been developed, the most promising of these provide little protection against the El Tor biotype of V. cholerae and probably no protection against the 0139 serotype.
V. cholerae only causes disease when colonization of the small bowel occurs. This colonization is also required for the induction of a localized immune response, an important aspect of development of effective vaccines. It is thought that interaction and uptake of bacteria by Peyers patches is the essential step in the localized immune response pathway. Thus, colonization of the intestine can be divided into two distinct steps: 1) interaction with Peyers patches and subsequent immune responses; and 2) interaction with enterocytes and subsequent disease processes (reactogenicity). Although the factors affecting colonization are not well understood, they are believed to include the TcpA pili and motility.